Small molecule screen employing patient-derived iPSC hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency

Abstract Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by inheritance of the SERPINA1-Z genetic variant (PiZ) leading to protein misfolding and liver toxicity. There remain no approved medicines for this disease. Here we report the results of a small molecule screen performed in patient-derived iPSC hepatocytes that identified Leucine-rich repeat kinase-2 (LRRK2), as a potentially new therapeutic target. Genetic deletion of LRRK2 in PiZ mice reduced both intrahepatic misfolded polymers and fibrosis leading us to test a library of commercially available LRRK2 inhibitors across several cell models. One of these molecules, CZC-25146, a candidate with favourable pharmacokinetic properties, reduced polymer load, increased normal AAT secretion and reduced inflammatory cytokines in both cells and the PiZ mouse. Mechanistically, this effect was achieved via inhibition of LRRK2 kinase activity and autophagy induction. These findings support the use of CZC-25146 (and potentially LRRK2 inhibitors more broadly) in hepatic proteinopathy disease research and as potential new therapies.